Peru is a South American nation with a growing and aging population of 31 million people with a life expectancy at birth of 76.7 years. The country is divided into 25 regions, 79% of the population is urban, and Lima, the capital, concentrates more than a third of the population.1 Although Peru is an upper-middle-income country, health expenditure represents only 5.1% of the gross domestic product, which is lower than the average of Latin America and the Caribbean (LATAM) (8.56%).2 Out-of-pocket health expenditure is 30.9%.3 Peru has a comprehensive National Cancer Plan and two population-based cancer registries in Lima and Arequipa. / Revisión por pares

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Thesis (M.D.)—Boston University

Inflammation is believed to play a pivotal role in the development of cancer and in particular lung cancer through both intrinsic and extrinsic pathways. This thesis aimed through 4 manuscripts to determine the role of lung-specific inflammation-related exposures as well as genetic variants (Single Nucleotide Polymorphism (SNPs)) in genes related to inflammation pathways in lung cancer risk. Risk factors of particular interest were lung diseases including emphysema, chronic bronchitis, pneumonia and tuberculosis. Data were collected from a Toronto-based case-control study and combined with data from the International Lung Cancer Consortium (17 studies for the non-genetic analyses and 6 studies for the genetic analyses). For non-genetic data, methods included, but were not limited to, unconditional logistic regression within single studies, Cox proportional hazards regression, meta-analytic techniques and pooled analyses techniques. For genetic data, additive models of association across 7,650 SNPs (selected based on role in inflammation) were pooled across studies and hierarchical modeling iv (HM) was used to incorporate prior functional information from various sources concerning the SNPs of interest. Within the Toronto study (manuscript 1) associations with increased lung cancer risk were observed for occupational exposures, previous lung diseases and a family history of cancer. The meta-analysis (manuscript 2) and pooled analysis (manuscript 3) showed relatively consistent associations between previous lung diseases and lung cancer risk across histology, gender and smoking categories. Results persisted when examining lung disease diagnoses made >10 or >20 years before cancer diagnosis. Our pathway-based analysis of inflammation-related variants and lung cancer risk using HM (manuscript 4) showed that HM is applicable to SNP analysis using pooled designs where heterogeneity can be incorporated into SNP priors. After HM a previously observed variant (rs2736100) and novel variant (rs2741354) were observed to be associated with lung cancer risk at corrected levels and replicated in an independent population. Taken together these results provide further evidence of both intrinsic and extrinsic factors affecting risk of lung cancer through inflammation.

Fer is a ubiquitously expressed non-receptor protein-tyrosine kinase that regulates normal physiology through signaling in a variety of cell types. Fer signals downstream of growth factor receptors frequently activated or amplified in human cancers and Fer has been identified as a positive regulator of cancer progression in the prostate and liver. Epidermal growth factor (EGF) receptor (EGFR) is frequently activated due to gene amplification or gain-of-function mutations in non-small cell lung carcinomas (NSCLC) leading to aggressive tumours that frequently metastasize. Since EGFR activates Fer, I tested whether Fer participates in EGFR-driven NSCLC cell migration, tumour progression and metastasis. Here, I show that Fer is expressed in cell lines derived from both normal lung epithelia and NSCLC and is activated following EGF treatment of NSCLC cells. To probe Fer function we used a lentiviral shRNA system to achieve stable knock-down (KD) of Fer in H1299 cells. Compared to control cells, Fer KD cells displayed a significant reduction in EGF-induced cell migration and invasion which correlated with reduced phosphorylation of the guanine nucleotide exchange factor Vav2. Consistent with Vav2 phosphorylation promoting Rac activation, we observed reduced localization of active, GTP- bound Rac1 to the leading edge of Fer KD cells treated with EGF. Tumour xenograft experiments were performed to test the role of Fer in NSCLC tumour progression and metastasis in immune compromised mice. Growth of primary tumours was normal, despite efficient Fer silencing in vivo. Interestingly, fewer spontaneous lung metastases were observed from subcutaneous Fer KD tumours compared to control. However, no differences were observed in lung seeding efficiency in experimental metastasis assays, suggesting that Fer may play a role in early stages of metastasis. Together, this study identifies Fer as a potential new therapeutic target for the treatment of EGFR-driven lung cancer metastasis. / Thesis (Master, Biochemistry) -- Queen's University, 2012-08-31 12:29:43.856

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No description available.

Inflammation is believed to play a pivotal role in the development of cancer and in particular lung cancer through both intrinsic and extrinsic pathways. This thesis aimed through 4 manuscripts to determine the role of lung-specific inflammation-related exposures as well as genetic variants (Single Nucleotide Polymorphism (SNPs)) in genes related to inflammation pathways in lung cancer risk. Risk factors of particular interest were lung diseases including emphysema, chronic bronchitis, pneumonia and tuberculosis. Data were collected from a Toronto-based case-control study and combined with data from the International Lung Cancer Consortium (17 studies for the non-genetic analyses and 6 studies for the genetic analyses). For non-genetic data, methods included, but were not limited to, unconditional logistic regression within single studies, Cox proportional hazards regression, meta-analytic techniques and pooled analyses techniques. For genetic data, additive models of association across 7,650 SNPs (selected based on role in inflammation) were pooled across studies and hierarchical modeling iv (HM) was used to incorporate prior functional information from various sources concerning the SNPs of interest. Within the Toronto study (manuscript 1) associations with increased lung cancer risk were observed for occupational exposures, previous lung diseases and a family history of cancer. The meta-analysis (manuscript 2) and pooled analysis (manuscript 3) showed relatively consistent associations between previous lung diseases and lung cancer risk across histology, gender and smoking categories. Results persisted when examining lung disease diagnoses made >10 or >20 years before cancer diagnosis. Our pathway-based analysis of inflammation-related variants and lung cancer risk using HM (manuscript 4) showed that HM is applicable to SNP analysis using pooled designs where heterogeneity can be incorporated into SNP priors. After HM a previously observed variant (rs2736100) and novel variant (rs2741354) were observed to be associated with lung cancer risk at corrected levels and replicated in an independent population. Taken together these results provide further evidence of both intrinsic and extrinsic factors affecting risk of lung cancer through inflammation.

5-year survival rate of patients with metastasized non-small cell lung cancer (NSCLC) who received chemotherapy was less than 5% (Kathryn C. Arbour, 2019). Our ability to provide survival status of a patient i.e. Alive or death at any time in future is important from at least two standpoints: a) from clinical standpoint it enables clinicians to provide optimal delivery of healthcare and b) from personal standpoint by providing patient’s family with opportunities to plan their life ahead and potentially cope with emotional aspect of loss of life. / Thesis / Master of Applied Science (MASc)

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